Novel Insights Into Cerebral Ischemic Pathophysiology In Humans

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Through our Natural History of Stroke study (Clinicaltrials.gov No. NCT00009243) we have studied over 2,700 participants in order to learn more about stroke and obtain information that may serve as the basis for future investigations. This protocol has allowed us to 1) establish a registry of patients with cerebrovascular disease (stroke); 2) characterize the natural history of acute stroke and transient ischemic attacks (TIA) an interruption of blood flow to the brain that causes stroke symptoms for a short period of time); and 3) evaluate the data to generate ideas for future studies. MRI has improved our ability to diagnose and stratify patients with acute stroke by providing highly sensitive and specific markers of the disease. Imaging based phenotypes of stroke increase objectivity; however, they remain a gross oversimplification of the complex biological system set in motion by a stroke. Next generation sequencing, with unprecedented improvement in throughput and speed, provides an opportunity to probe the complex biological response to stroke in patients stratified using acute MRI. Based on the premise that the biology responsible for the imaging abnormalities will be reflected in differential gene expression and micro RNA in peripheral blood, next generation sequencing will be used to identify and characterize the biological systems relevant to the imaging phenotype. A systems biology approach will be developed to better describe stroke, and hopefully, better differentiate those patients in whom we can expect a favorable response to an intervention, from those at risk of further deterioration. Imaging based predictors of stroke outcome and response to therapy are necessary for the utility and validation of imaging biomarkers in drug development. Useful models are those that can distinguish patients destined for good outcomes versus poor outcomes, those who received effective therapy from those who did not, and treatment responders from non-responders. We are investigating several predictive models. These prediction models may be useful for the development, selection and use of acute therapies. We found that change in lesion volume from pre-treatment diffusion-weighted imaging to post-treatment FLAIR can discriminate between patients destined for good and poor outcomes when treated with effective acute stroke therapy, i.e., intravenous tPA. Thus, lesion volume change may be a useful marker of clinical response in the stroke therapy development. As part of the Stroke Branch, there is significant interested in vascular cognitive impairment and white matter disease, originally initiated by the Neuro Vascular Brain Imaging Unit (NVBI). Investigators continue to access data and images to study white matter disease and BBB disruption. A new protocol was initiated for this purpose (PI Clinton Wright), but the pandemic caused a pause in all study related activity. Work continues to study the impact of stroke on white matter disease and cognitive impairment through data collected as part of this project. During this past fiscal year, our efforts have largely been focused as follows: Minor stoke (TIMES): Patients often present to the emergency department with very mild and potentially non-disabling or fluctuating symptoms. These may lead to delayed diagnosis and/or withholding of treatment. We are prospectively studying the use of MRI in identifying those patients who would most likely benefit from intervention. Enrollment is continuing and the first TIMES manuscript was published this year. Secondary damage post mechanical embolectomy (GUARDS): In patients with large vessel occlusion, one of the most severe categories of stroke, removal of the clot by mechanical means has proven to be efficacious. However, many patients go on to poor outcome despite successful mechanical intervention. We are using MRI to study and classify the kind of injury that occurs following recanalization of the large vessel. This past year, we have published, through collaboration, a seminal study on the genesis of edema following vascular injury. Significant progress has been made in our prospective observational study to identify markers of blood-brain barrier disruption, paradoxical increased blood flow, edema, and hemorrhage. We have designed a trial to treat edema and are actively working on procuring the biologic needed for the intervention Early disruption of the blood brain barrier (HARM): This has been a long-standing project within the program with numerous publications. In conjunction with our research in traumatic brain injury, we have found evidence of leakage of contrast agent into fluid filled spaces surrounding vessels near the meninges. We can detect the enhancement immediately after contrast administration. A manuscript is under review, a second retrospective study of high-resolution imaging is under way. We are designing a prospective study to compare acute stroke patients to a control population, and measure the rate of clearance as a marker of impaired cerebral lymphatics